The use of digitalis glycosides in the treatment of congestive heart failure has long been closely associated with cardiac toxicity. However, data from our laboratory demonstrate that two cardiac glycosides having a 4-aminosugar attached to digitoxigenin (ASI-222 and ASI-254) have a greater positive inotropic action on the heart and a significantly greater therapeutic index (TI) than ouabain or digoxin (and by implication, all other cardiac glycosides). The objectives of our proposed research are: 1) to establish more completely the therapeutic index for ASI-222 and ASI-254 and determine it for other aminosugar glycosides by using various preparations from several different species, 2) to establish the optimum structural configuration and site of amino-substitution on a sugar for such a cardiac glycoside which yields the greatest TI, and 3) to determine the basis for this salutary dissociation between efficacy and toxicity. We propose to accomplish our objectives by: 1) establishing therapeutic and toxic effects for the aminosugar cardiac glycosides on isolated cat papillary, isolated rabbit atrial muscle and in open and closed-chest dogs, 2) studying the actions of certain other aminosugar glycosides containing either another genin and/or different amine placements on the sugars (synthesized on contract) on the test systems listed above in the quest of the agent with optimum activity (TI), and 3) determining the relationships of the therapeutic and toxic effects of aminosugar cardiac glycosides to Na ion, K ion - ATPase activity, certain pharmacokinetic parameters, important cardiac electrical events and to the autonomic nervous system. Our proposed research should produce a clinically useful cardiac glycoside which has a greater degree of safety than those which are now available.